Letter | Published:

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol

Nature volume 519, pages 370373 (19 March 2015) | Download Citation

Abstract

Resveratrol is reported to extend lifespan1,2 and provide cardio-neuro-protective3, anti-diabetic4, and anti-cancer effects3,5 by initiating a stress response2 that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions6, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD+-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS–PARP1–NAD+ collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites7, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD+-dependent dimension to the physiological mechanism of resveratrol.

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Data deposits

X-ray structure coordinates of resveratrol-bound TyrRS and l-Tyr bound TyrRS have been deposited in Protein Data Bank under accession numbers 4Q93 and 4QBT, respectively.

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Acknowledgements

This work was supported in part the National Cancer Institute grant CA92577, by a fellowship from the National Foundation for Cancer Research, and by aTyr Pharma through an agreement with The Scripps Research Institute. We thank the The Scripps Research Institute mouse facility for their efforts for this project. We also thank P. Chang for the ZZ-PARP1 clone, and the PARG and PARG-MT proteins, and Y. Shi for independently repeating some of the key experiments. We thank P. Chang, J. H. Chung, L. Guarente, L. Krauss, D. Sinclair, and C. Westphal for comments and suggestions on this work.

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Affiliations

  1. The Skaggs Institute for Chemical Biology, The Scripps Laboratories for tRNA Synthetase Research, Department of Molecular and Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Mathew Sajish
    •  & Paul Schimmel
  2. The Scripps Florida Research Institute, 130 Scripps Way, Jupiter, Florida 33458, USA

    • Paul Schimmel

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Contributions

M.S. and P.S. conceived the idea, designed the research, analysed the data, and wrote the manuscript. M.S. performed the experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Paul Schimmel.

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https://doi.org/10.1038/nature14028

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